Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder

PLoS One. 2015 Aug 14;10(8):e0134572. doi: 10.1371/journal.pone.0134572. eCollection 2015.

Abstract

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / physiopathology*
  • Behavior, Animal / physiology
  • Chromosomes, Mammalian / genetics*
  • Cognition / physiology
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Sequence Deletion
  • Vocalization, Animal / physiology

Substances

  • CNTNAP2 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins

Grant support

This project was funded by the Simons Foundation and Roche as a contract to PsychoGenics. Simons Foundation, Roche, and PsychoGenics contributed to the conception and design of the experiments and to the writing of the manuscript. PsychoGenics provided support in the form of salaries for authors DB, PK, DH, KC, LT, TH, ES and VA. Roche provided support in the form of salaries for authors MS, WS, AG and BB. The specific roles of these authors are articulated in the ‘author contributions’ section. All aspects of experimental design, data collection and analysis, and decision to publish the manuscript were made jointly by Roche, PsychoGenics, and the Simons Foundation.